guest ::
| Home > Publications database > Zur praktisch trägerfreien F-018 Fluorierung von Proteinen, Peptiden und Tyrosin |
| Home > Publications database > Zur praktisch trägerfreien F-018 Fluorierung von Proteinen, Peptiden und Tyrosin |
| Book/Report | FZJ-2019-01394 |
1996
Forschungszentrum Jülich GmbH Zentralbibliothek, Verlag
Jülich
Please use a persistent id in citations: http://hdl.handle.net/2128/21619
Report No.: Juel-3206
Abstract: Radiolabeled amino acids, biospecific peptides and proteins, including monoclonal antibodies and their fragments are widely used as imaging and therapeutic agents, particularly for tumor targeting. To take advantage of the nearly ideal nuclidic properties of fluorine-18 (T$_{1/2}$ = 110 min, E$_{beta}$+= 635 keV) for non-invasive diagnostic imaging with positron emission tomography (PET), suitable $^{18}$F-fluorination procedures via prosthetic group labeling and subsequent conjugation for the above mentioned classes of compounds were investigated and compared with respect to synthesis time, radiochemical yield (RCY), suitability for automation, in vivostability and preservation ofthe biological activity ofthe labeled biomolecules. For the $^{18}$F-fluorination of proteins, such as transferrin, human serum albumin, avidin and various immunoglobulins three methods were investigated, i.e. classical acylation using N-succinimidyl 4-[$^{18}$F]fluorobenzoate ([$^{18}$F]SFB), nitrophenyl 2-[$^{18}$F]fluoropropionate ([$^{18}$F]NPFP) and a photochemical conjugation using 4-azidophenacyl [$^{18}$F]fluoride ([$^{18}$F]APF). For this purpose, [$^{18}$F]SFB and [$^{18}$F]NPFP were synthesized in three steps, the latter compound Via an improved method using O-(N-succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate as activating agent (35 min, 50% RCY). Preparation of [$^{18}$F]APF via fluorine-for-bromine exchange on 4-azidophenacyl bromide was achieved within 15 min with a RCY ofup to 70%. Compared to [$^{18}$F]APF, protein labeling with [$^{18}$F]NPFP and [$^{18}$F]SFB gave rise toconsiderably higher RCY of up to 90%. The conjugation yields using [$^{18}$F]NPFP in the presence of I-hydroxy benzotriazole depend on the relative lysine, tyrosine and histidine content of the proteins used, whereas photochemical conjugation with [$^{18}$F]APF, as well as acylation with [$^{18}$F]SFB, predominantly depend on the lysine content. Due to competing O-acylation of tyrosine residues, [$^{18}$F]fluoropropionylated human serum albumin was partially unstable even under slightly basic conditions. Biodistribution studies with $^{18}$F-labeled human serum albumin in NMRI mice revealed the highest in vivo stability for the [$^{18}$F]SFB conjugate. Subsequently, the applicability of these methods to smaller bioactive peptides was demonstrated. Thus, [$^{18}$F]fluoropropionyl-octreotide, a somatostatin receptor ligand, and [$^{18}$F]fluorobenzoyl-apamin, a selective blocker of calcium dependent potassium channels, were prepared with RCY ofup to 70% (based on the acylation agent). In addition, both compounds were biologically evaluated. Whereas the binding of the fluorinated octreotide to somatostatin receptors in pancreas, pituitary and adrenals of NMRl mice could be blocked by pretreatment with unlabeled octreotide, lack of displacement at later times indicated internalization of the radioligand. As a potential tracer for the cerebral amino acid transport system, O-(2-[$^{18}$F]fluoroethyl)tyrosine was prepared by O-(2-[$^{18}$F]fluoroethylation of fully protected tyrosine and unprotected tyrosine using 2-[$^{18}$F]fluoroethyltosylat with RCY of 35-39%. The tracer showed high and continous uptake in mice brain reaching 2.5% injected dose/g at 60 minutes and exhibited high in vivo stability.
|
The record appears in these collections: |
PDF
PDF (PDFA)